Osteopontin is an arginine-glycine-aspartic acid (RGD)-containing glycoprotein that interacts with integrins and CD44 as major receptors. It is a multifunctional protein involved in bone mineralization, cell adhesion, cell migration, chronic inflammatory disease and transformation. Proteolytic cleavage by thrombin and matrix metalloproteinases close to the integrin-binding Arg-Gly-Asp sequence modulates the function of OPN and its integrin binding properties. Thrombin-cleaved fragments of Osteopontin are overexpressed in malignant glial tumors and provide a molecular niche with survival advantage and provide a novel substrate for plasmin and cathepsin D.